Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

Blood. 2016 Oct 20;128(16):2007-2016. doi: 10.1182/blood-2016-04-713289. Epub 2016 Sep 1.

Abstract

A normal hemostatic response to vascular injury requires both factor VIII (FVIII) and von Willebrand factor (VWF). In plasma, VWF and FVIII normally circulate as a noncovalent complex, and each has a critical function in the maintenance of hemostasis. Furthermore, the interaction between VWF and FVIII plays a crucial role in FVIII function, immunogenicity, and clearance, with VWF essentially serving as a chaperone for FVIII. Several novel recombinant FVIII (rFVIII) therapies for hemophilia A have been in clinical development, which aim to increase the half-life of FVIII (∼12 hours) and reduce dosing frequency by utilizing bioengineering techniques including PEGylation, Fc fusion, and single-chain design. However, these approaches have achieved only moderate increases in half-life of 1.5- to 2-fold compared with marketed FVIII products. Clearance of PEGylated rFVIII, rFVIIIFc, and rVIII-SingleChain is still regulated to a large extent by interaction with VWF. Therefore, the half-life of VWF (∼15 hours) appears to be the limiting factor that has confounded attempts to extend the half-life of rFVIII. A greater understanding of the interaction between FVIII and VWF is required to drive novel bioengineering strategies for products that either prolong the survival of VWF or limit VWF-mediated clearance of FVIII.

Publication types

  • Review

MeSH terms

  • Factor VIII* / pharmacokinetics
  • Factor VIII* / therapeutic use
  • Half-Life
  • Hemophilia A / blood
  • Hemophilia A / drug therapy
  • Humans
  • Recombinant Fusion Proteins* / pharmacokinetics
  • Recombinant Fusion Proteins* / therapeutic use
  • von Willebrand Factor / metabolism*

Substances

  • Recombinant Fusion Proteins
  • von Willebrand Factor
  • F8 protein, human
  • Factor VIII